Giannini-trombosi venosa profonda diagnosi e

Giornate di Aggiornamento in Oncologia
1°Edizione
“PROBLEMATICHE ACUTE DEL PAZIENTE
ONCOLOGICO”
Trombosi venosa profonda: diagnosi e trattamento
Giannini
SDO Cardio-Angiologia
Introduction
Within the last six years 31
practice guidelines and major
reviews on cancer and venous
thromboembolism (VTE) have
been published in international
oncology journals.
Why has this subject become so
noteworthy?
Introduction
In parallel with this epidemiologic development, the
number of cancer patients with VTE has increased.
VTE jeopardizes the net benefit of any new drug
and its future market approval,not to mention the
economic impact from the VTE itself.
VTE is frequent and serius
►
►
The overall risk in cancer
patients is 4–7 fold higher
than
in
non-cancer
patients
Some10–20% of cancer
patients develop VTE
during the course of their
disease
►
VTE is a signum
malum:a significantly
worse
prognosis
compared to patients
without cancer
Mechanisms of CancerCancer-Induced Thrombosis:
The Interface
1. Pathogenesis
Pathogenesis?
?
2. Biological significance?
3. Potential importance for cancer therapy?
Pathogenesis of Thrombosis in Cancer
A Modification of Virchow’s Triad
1. Stasis
●
●
Prolonged bed rest
Extrinsic compression of blood vessels by tumor
2. Vascular Injury
●
●
●
●
Direct invasion by tumor
Prolonged use of central venous catheters
Endothelial damage by chemotherapy drugs
Effect of tumor cytokines on vascular endothelium
3. Hypercoagulability
●
●
●
Tumor-associated procoagulants and cytokines (tissue factor, CP,
TumorTNFα
TNF
α, ILIL-1β, VEGF, etc.)
Impaired endothelial cell defense mechanisms (APC resistance;
deficiencies of AT, Protein C and S)
Enhanced selectin/integrinselectin/integrin-mediated, adhesive interactions
between tumor cells,vascular endothelial cells, platelets and host
macrophages
Interface of Clotting Activation
and Tumor Biology
FVII/FVIIa
Tumor
Cell
TF
Blood Coagulation
Activation
VEGF
THROMBIN
FIBRIN
Angiogenesis
ILIL-8
PAR--2
PAR
Angiogenesis
TF
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis, 2005
Mechanisms of CancerCancer-Induced Thrombosis:
Clot and Cancer Interface
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer therapy?
therapy?
Activation of Blood Coagulation in Cancer
Biological Significance?
►
Epiphenomenon?
Epiphenomenon
?
Is this a research
generic secondary
4 Recent
supports event
the where
concept that
thrombosis
is an incidentalisfinding
oncogenic
transformation
closely linked to
procoagulant
conversion
of
the
tumor
microenvironment.
or, is clotting activation . . .
4 Hypercoagulability seems to confer a growth
advantage to the tumor, supports cell motility, and
invasion
of healthy
tissues.
► A Primary
Event?
Linked to malignant transformation
Mechanisms of CancerCancer-Induced Thrombosis:
Implications
1. Pathogenesis?
2. Biological significance?
3. Potential importance for cancer
therapy?
Cancer and Thrombosis
State--ofState
of-the
the--Science Update
Key Questions
1. Does activation of blood coagulation affect
the biology of cancer positively or negatively?
2. Can we treat tumors more effectively using
coagulation protein targets?
3. Can anticoagulation alter the biology of cancer?
Cancer and Thrombosis
State--ofState
of-the
the--Science Update
Tentative Answers
1.
Epidemiologic evidence is suggestive that VTE is a
bad prognostic sign in cancer
2.
Experimental evidence is supportive of the use of
antithrombotic strategies for both prevention of
thrombosis and inhibition of tumor growth
3.
Results of recent, randomized clinical trials of LMWH
in cancer patients indicate superiority in preventing
recurrent VTE and suggest increased survival (not
due to just preventing VTE)—
VTE)— “Titillating”
Coagulation Cascade and Tumor Biology
TF
ClottingClottingdependent
VIIa
ClottingClottingindependent
Thrombin
Xa
ClottingClottingindependent
?
ClottingClottingdependent
Fibrin
Clottingdependent
PARs
Angiogenesis, Tumor
Growth and Metastasis
LMWH (e.g. dalteparin)
Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
Cancer and Thrombosis
Diagnosis of VTE
Diagnosis of VTE
Diagnostica ultrasonografica
• L’ultrasonografia (eco color Doppler)
va considerata la metodica diagnostica
•
di prima scelta per la diagnosi della TVP
prossimale nel paziente a rischio
intermedio o alto.
• Il criterio diagnostico validato è la
incomprimibilità (CUS).
Dosaggio dei D-Dimeri
• Per il dosaggio dei DD è necessario utilizzare metodi
sensibili e per i quali siano disponibili valori di cut-off
ben determinati mediante studi clinici su pazienti con
TVP comprovata.
• Il test non va considerato isolatamente ma va integrato
con informazioni di ordine clinico e strumentale.
• Un risultato negativo del test in soggetti nei quali
l’intervallo di tempo tra l’ insorgenza dei sintomi e il
controllo di laboratorio sia superiore a 7-10 giorni
non va considerato come conclusivo.
Linee guida SISET-SIAPAV-SIDV 2000 – CIF 2000-2003
Diagnosis of VTE
Cancer and Thrombosis
VTE Treatment
Standard Treatment of VTE
Can We Do Better Than This?
Initial treatment
5 to 7 days
LMWH or UFH
Long-term therapy
Vitamin K antagonist (INR 2.0 - 3.0)
> 3 months
Recurrent VTE in Cancer
Subset Analysis of the Home Treatment Studies
(UH/VKA vs. LMWH/VKA)
Recurrent VTE
Events per 100 patient years
Malignant
Non
Non-- Malignant
27.1
9.0
Hutten et.al. J Clin Oncol 2000;18:3078
P value
0.003
Recurrent VTE in Cancer
Subset Analysis of the Home Treatment Studies
Major Bleeding
Events per 100 patient years
Malignant
NonNonmalignant
13.3
2.1
Hutten et.al. J Clin Oncol 2000;18:3078
P-value
0.002
Oral Anticoagulant Therapy
in Cancer Patients: Problematic
► Warfarin
●
●
●
●
►
therapy is complicated by:
Increased risk of both recurrence and bleeding
Difficulty maintaining tight therapeutic control, due
to anorexia, vomiting, drug interactions, etc.
Frequent interruptions for thrombocytopenia and
procedures
Difficulty in venous access for monitoring
Is it reasonable to substitute longlong-term LMWH
for warfarin ? When? How? Why?
Treatment of CancerCancer-Associated VTE
Study
Design
Length of
Therapy
(Months)
N
Recurrent
VTE
(%)
Major
Bleeding
(%)
Death
(%)
CLOT Trial
(Lee 2003)
Dalteparin
OAC
6
336
336
9 0.002
17
6
4
NS
39 NS
41
CANTHENOX
(Meyer 2002)
Enoxaparin
OAC
3
67
71
11 0.09
21
7
16
0.09
11
0.03
23
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
3
80
87
6
11
6
8
NS
23 NS
22
ONCENOX
(Deitcher ISTH
2003)
Enox (Low)
Enox (High)
OAC
6
32
36
34
3.4
NS
3.1
6.7
0.03
NS
NR
Initial management of a first episode of cancer-associated VTE
Choice of anticoagulant
►
no difference in efficacy between LMWH and UFH in patients with cancer
►
a statistically significant reduction in mortality risk with LMWH at 3 months of follow-up
has been noted.
►
LMWH vs UFH : lower cost (because hospitalization and laboratory monitoring are not
required) and simple dosing (because the total daily dose is based on body weight),
lower risk for heparin-induced thrombocytopenia (HIT).
►
Data on the use of fondaparinux: In the Matisse trials, the 3-month rate for
symptomatic, recurrent VTE was higher for fondaparinux vs enoxaparin in DVT
treatment (12.7% vs 5.4%) but was lower for fondaparinux vs UFH in PE treatment
(8.9% vs 17.2%).
►
Like LMWH, fondaparinux is administered as a once-daily, weight-based
subcutaneous injection. Rarely associated with the development of drug-induced
thrombocytopenia
►
Barriers to its use in oncology patients include a relatively long half-life of 17 to 21
hours, the lack of a reversal agent, and 100% dependence on renal clearance.
Initial management of a first episode of cancer-associated VTE
Choice of anticoagulant
►
LMWH is the recommended anticoagulant for the initial therapy of VTE in most
patients with cancer
►
UFH can be used in those with severe renal impairment (creatinine clearance
[CrCl],30 mL/min) given its shorter half-life, reversibility with protamine sulfate,
and dependence on hepatic clearance.
►
Fondaparinux is a reasonable choice in patients with a history of HIT.
Initial management of a first episode of cancer-associated VTE
Use of thrombolysis in cancer-associated VTE
►
the safety, cost-effectiveness, and longterm benefit of
thrombolysis remain uncertain
►
it is prudent to review each patient carefully and
exclude patients with central nervous system lesions
or other risk factors for bleeding
Long-term management of a first episode of cancer-associated VTE
Choice of anticoagulant
►
LMWH is recommended for both initial and long-term anticoagulation in cancerassociated thrombosis by major consensus guidelines
►
If LMWH is unavailable, the American Society of Clinical Oncology (ASCO) 2013
VTE Prevention and Treatment Guideline recommends the use of VKA with a
target INR of 2 to 3 as an acceptable alternative
Long-term management of a first episode of cancer-associated VTE
Duration of anticoagulation and anticoagulant options for extended therapy
►
The decision regarding the continuation of anticoagulation beyond the first 3 to 6 months is
largely based on weighing the risk for recurrent thrombosis against the risk of major
bleeding.
►
it has been generally accepted that continuing anticoagulation is warranted in patients with
ongoing risk factors such as metastatic or progressive disease and ongoing chemotherapy
►
The choice of anticoagulant for extended anticoagulant therapy (beyond 6 months) also has
not been investigated
►
As with duration of therapy, the anticoagulant of choice needs to be discussed with each
patient and individualized
Long-term management of a first episode of cancer-associated VTE
Anticoagulation in patients with renal impairment
►
Renal insufficiency is associated with some cancers (e.g.multiple myeloma),
nephrotoxic agents (e.g.cisplatin chemotherapy),and renovascular disease in the
elderly.
►
LMWHs accumulate when the creatinine clearance deteriorates, and dosage
adjustments for renal failure are available for each approved LMWH.
►
With severe renal insufficiency (creatinine clearance o 30 ml/min),unfractionated
heparin should be substituted for LMWH, and doses adjusted based on the
activated partial thromboplastin time.
Long-term management of a first episode of cancer-associated VTE
Inferior vena cava (IVC) filters
IVC filters should be restricted to patients with acute VTE
and contraindications to anticoagulation.
►
Rates of recurrent VTE up to 32% have been reported in patients with cancer treated with
IVC filters, and fatal PE after filter insertion has been well documented.
►
Insertion problems occur in 4% to 11% of patients
►
Long-term adverse effects such as thrombosis of the IVC or lower extremity veins occur in
4% to 32%.
►
absence of data to support their efficacy
►
Their use in patients with recurrent thrombotic events despite standard anticoagulant
therapy goes against biological rationale
►
The use of IVC filters may provide a sense of false security regarding the risk for recurrent
PE, causing delays or discontinuation of anticoagulant therapy.
If retrievable filters are placed, efforts should be made to remove the device and
reinitiate anticoagulation as soon as the high-risk period for bleeding has passed
Treatment of recurrent VTE during
anticoagulant therapy
Treatment of incidental VTE
►
incidental VTE rates of up to 6%
►
represents a significant proportion of thrombotic
complications in patients with cancer, comprising up
to 60% in large series
►
the occurrence of incidental VTE can have a negative
impact on both patient quality of life and clinical
outcome
►
Whether anticoagulation is indicated or beneficial in
patients with incidental VTE remains controversial
►
Nonetheless, based on published literature to date, it
is recommended that patients with incidental DVT
and PE receive therapeutic anticoagulation if there
are no contraindications
Treatment of cancer-associated thrombosis in
patients with a high risk of bleeding
►
Bleeding is frequently associated with anticoagulant use in patients with
cancer : 12.4%, with one third of the bleeding events occurring during the
initial phase of anticoagulation
►
Features specific to oncology patients that contribute to bleeding include:
The extent, location, and histologic features of the cancer
need for invasive diagnostic or treatment procedures
the development of thrombocytopenia from chemotherapy or from the
underlying malignancy.
Other comorbidities : renal impairment and coagulopathy from liver
dysfunction, disseminated intravascular coagulopathy, or sepsis
-
►
all patients require an individualized assessment of their bleeding risk
before the initiation of anticoagulation
►
Current and potential bleeding sources should be identified and managed,
and the risk of serious bleeding should be weighed against the severity of
the thrombotic event and risk for recurrent VTE
NCCN Practice Guidelines
in VTE Disease
Relative Contraindications to Prophylactic or
Therapeutic Anticoagulation
►
►
►
►
►
►
►
►
►
Recent CNS bleed, intracranial or spinal lesion at high risk for bleeding
Active bleeding (major): more than 2 units transfused in 24 hours
Chronic, clinically significant measurable bleeding > 48 hours
Thrombocytopenia (platelets < 50,000/mcL)
Severe platelet dysfunction (uremia, medications, dysplastic
hematopoiesis)
Recent major operation at high risk for bleeding
Underlying coagulopathy
Clotting factor abnormalities
- Elevated PT or aPTT (excluding lupus inhibitors)
- Spinal anesthesia/lumbar puncture
High risk for falls
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
Treatment of cancer-associated thrombosis in
patients with a high risk of bleeding
►
In patients with minor bleeding anticoagulation may be
continued as long as close follow-up is available.
►
In patients with absolute contraindications to
anticoagulation:
-
anticoagulants should be withheld.
-
follow-up imaging should be performed to assess for
thrombus progression
-
IVC filter insertion can be considered.
Treatment of cancer-associated thrombosis in
patients with a high risk of bleeding
►
If severe cancer- or
chemotherapy-induced
thrombocytopenia is
present:
(<1 month)
(>1 month)
Treatment of cancer-associated thrombosis in
patients with a high risk of bleeding
►
Management of VTE in patients with intracranial malignancies
►
No randomized controlled data exist for management of
patients with primary or metastatic intracranial tumors and
VTE
►
small retrospective studies indicate that anticoagulation can
be safely used.
►
The ASCO 2013 VTE Guideline recommends treating patients
with intracranial malignancies with standard anticoagulation
Treatment of catheter-related thrombosis
►
To date, published data and clinical experience suggest that
catheter-related thrombosis is associated with a low risk for
thrombosis recurrence and post-thrombotic syndrome
►
conservative treatment is recommended
►
A sensible approach is to remove the catheter only if :
-
(1) central venous access is no longer required;
-
(2) the device is nonfunctional or defective;
-
or (3) line-related sepsis is suspected or documented
therapeutic anticoagulation should be given using either LMWH alone or LMWH
followed by warfarin therapy.
A short period of anticoagulation (3-5 days of LMWH) may even salvage some
thrombosed catheters and obviate the need to remove and replace the line.
Anticoagulation is recommended for a minimum of 3 months and while the catheter
remains in place.
Use of NOACs in cancer-associated
thrombosis
►
No studies have specifically addressed the treatment of cancerassociated VTE using these direct inhibitors
►
interactions do exist with some chemotherapeutic agents
►
gastrointestinal tract problems in patients with cancer can potentially
alter drug delivery and absorption
►
the current ASCO Guideline does not recommend the use of these
new agents
CONCLUSIONI
Lyman et al, JCO 2013
DVT, PE Diagnosis and Treatment
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
Thrombosis in Malignancy
7TH ACCP Consensus Conference Recommendations
Initial Phase
Chronic Phase
5-7 days
Dalteparin 200/kg q24h
(GRADE 1A)
Continue anticoagulation
(warfarin or LMWH) long-term or
until malignancy resolves
(GRADE 1C)
5 - 7 days
3 - 6 mos
6 mos - indefinite
Subacute Phase
3 - 6 months
PRESS RELEASE:
May 2, 2007
Dalteparin 150 units/kg q24h
FDA Approves Dalteparin as First LowLow-Molecular Weight Heparin for Extended
(GRADE
1A)
Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer
Buller HR, et al. Chest 2004; 126 (suppl 3): 401s401s-428s
NCCN Practice Guidelines—
Guidelines—Venous
Thromboembolic Disease
Therapeutic Anticoagulation Treatment for
DVT, PE, and CatheterCatheter-Associated Thrombosis
Immediate
► LMWH
- Dalteparin (200 units/kg subcutaneous daily)
- Enoxaparin (1 mg/kg subcutaneous every 12 hrs)
-Tinzaparin (175 units/kg subcutaneous daily)
►
Pentasaccharide
- Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50[50-100 lg]; 10 mg [>100 kg]
subcutaneous daily
►
Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour,
target aPTT to 2.02.0-2.9 x control)
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCCN Practice Guidelines—
Guidelines—Venous
Thromboembolic Disease
Therapeutic Anticoagulation Treatment for
DVT, PE, and CatheterCatheter-Associated Thrombosis
Long Term
►
►
LMWH is preferred as monotherapy without warfarin in patients with
proximal DVT or PE and prevention of recurrent VTE in patients with
advanced or metastatic cancer
Warfarin (2.5(2.5-5 mg every day initially, subsequent dosing based on INR
value; target INR 2.02.0-3.0)
Duration of Long Term Therapy
►
►
►
Minimum time of 33-6 mo for DVT and 6
6--12 mo for PE
Consider indefinite anticoaugulation if active cancer or persistent risk
factors
For catheter associated thrombosis, anticoagulate as long as catheter
is in place and for 11-3 mo after catheter removal
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
►
What is the best treatment for patients with
cancer with established VTE to prevent recurrent
VTE ?
●
LMWH is the preferred approach for the initial 55-10
days.
LMWH, given for at least 6 months, is the preferred
for longlong-term anticoagulant therapy.
After 6 months, anticoagulation therapy should be
considered for select patients.
For CNS malignancies, elderly patients
anticoagulation is recommended with careful
monitoring and dose adjustment.
●
●
●
Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505.
►
Should patients with cancer receive
anticoagulants in the absence of
established VTE to improve survival?
●
“Anticoagulants are not recommended to improve
survival in patients with cancer without VTE.”
Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505.
CLOT: Landmark Cancer/VTE Trial
Dalteparin
Dalteparin
CANCER PATIENTS WITH
Randomization
ACUTE DVT or PE
[N = 677]
Dalteparin
Oral Anticoagulant
►
Primary Endpoints: Recurrent VTE and Bleeding
►
Secondary Endpoint:
Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Landmark CLOT Cancer Trial
Probability of Recurrent VTE, %
Reduction in Recurrent VTE
25
Recurrent VTE
Risk reduction = 52%
p-value = 0.0017
20
OAC
15
10
Dalteparin
5
0
0
Lee, Levine, Kakkar, Rickles et.al. N Engl
J Med, 2003;349:146
30
60
90
120
150
Days Post Randomization
180
210
Bleeding Events in CLOT
Dalteparin
OAC
N=338
N=335
Major bleed
19 ( 5.6%)
12 ( 3.6%)
0.27
Any bleed
46 (13.6%)
62 (18.5%)
0.093
* Fisher’s exact test
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
P-value*
Treatment and 2°
2° Prevention of VTE
in Cancer – Bottom Line
New Development
►
New standard of care is LMWH at therapeutic doses
for a minimum of 33-6 months (Grade 1A
recommendation—
recommendation
—ACCP)
►
NOTE: Dalteparin is only LMWH approved (May,
NOTE:
2007) for both the treatment and secondary
prevention of VTE in cancer
►
Oral anticoagulant therapy to follow for as long as
cancer is active (Grade 1C recommendation—
recommendation—ACCP)
Buller et.al. Chest Suppl 2004;126:401S2004;126:401S-428S
CLOT 1212-month Mortality
All Patients
Probability of Survival, %
100
90
80
70
Dalteparin
60
OAC
50
40
30
20
10
0
HR 0.94 PP-value = 0.40
0
30 60 90 120
180
240
300
Days Post Randomization
Lee A, et al. ASCO. 2003
360
Anti-Tumor Effects of LMWH
AntiCLOT 1212-month Mortality
Patients Without Metastases (N=150)
Probability of Survival, %
100
Dalteparin
90
80
70
OAC
60
50
40
30
20
10
HR = 0.50 PP-value = 0.03
0
0
30 60 90 120 150 180
240
300
Days Post Randomization
Lee A, et al. ASCO. 2003
360
LMWH for Small Cell Lung Cancer
Turkish Study
►
84 patients randomized: CEV +/+/- LMWH (18 weeks)
►
Patients balanced for age, gender, stage, smoking history,
ECOG performance status
Chemotherapy
plus Dalteparin
Chemo alone
P-value
1-y overall survival, %
51.3
29.5
0.01
2-y overall survival, %
17.2
0.0
0.01
Median survival, m
13.0
8.0
0.01
CEV = cyclophosphamide, epirubicin, vincristine;
LMWH = Dalteparin, 5000 units daily
Altinbas et al. J Thromb Haemost 2004;2:1266.
Rate of Appropriate Prophylaxis, %
VTE Prophylaxis Is Underused
in Patients With Cancer
100
90
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Major
Surgery2
89
80
70
60
Cancer:
Surgical
Major
Abdominothoracic
Surgery (Elderly)3
52
50
38
40
30
Medical
Inpatients4
Confirmed DVT
(Inpatients)5
42
33
Cancer:
Medical
20
10
5
0
FRONTLINE FRONTLINE:
Surgical
Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
Stratton
Bratzler
Rahim
DVT FREE
4. Rahim SA et al. Thromb Res. 2003;111:215-219
5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
Clotting, Cancer, and Clinical Strategies
Venous Thromboembolism (VTE)
Prophylaxis in the
Cancer Patient and Beyond
Guidelines and Implications for Clinical Practice
John Fanikos, RPh, MBA
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA
Outline of Presentation
►
Guidelines for VTE prevention
►
Performance to date
►
Opportunities for improvement
►
Guidelines for VTE Treatment
►
Performance to date
• www.nccn.org
• NCCN Clinical Practice Guidelines in
Oncology™
• “…The panel of experts includes medical
and surgical oncologists, hematologists,
cardiologists, internists, radiologists. And a
pharmacist.”
• www.asco.org
•Recommendations for VTE Prophylaxis &
Treatment in Patients with Cancer
2004 ACCP Recommendations
Cancer patients undergoing surgical procedures receive prophylaxis that is
appropriate for their current risk state (Grade 1A)
●
General, Gynecologic, Urologic Surgery
• Low Dose Unfractionated Heparin 5,000 units TID
• LMWH > 3,400 units Daily
– Dalteparin 5,000 units
– Enoxaparin 40 mg
– Tinzaparin 4,500 units
• GCS and/or IPC
Cancer patients with an acute medical illness receive prophylaxis
that is appropriate for their current risk state (Grade 1A)
• Low Dose Unfractionated Heparin
• LMWH
Contraindication to anticoagulant prophylaxis (Grade 1C+)
• GCS or IPC
1A is the highest possible grade
Indicates that benefits outweigh risks, burdens, and costs,
with consistent RCT level of evidence
Geerts WH et al. Chest. 2004;126(suppl):338S-400S
NCCN Practice Guidelines in VTE Disease
At Risk Population
►
►
►
►
►
►
►
►
►
►
►
►
►
►
Adult patient
Diagnosis or
clinical
suspicion of
cancer
Inpatient
Relative contracontraindication to
anticoagulation
treatment
RISK FACTOR ASSESSMENT
Age
Prior VTE
Familial thrombophilia
Active cancer
Trauma
Major surgical procedures
Acute or chronic medical illness requiring
hospitalization or prolonged bed rest
Central venous catheter/IV catheter
Congestive heart failure
Pregnancy
Regional bulky lymphadenopathy with
extrinsic vascular compression
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
Initial Prophylaxis
Continue
Prophylaxis
After
Modifiable
risk factors: Lifestyle,
Discharge
?
smoking, tobacco, obesity,
Prophylactic anticoagulation
therapy (category 1) + sequential
compression device (SCD)
Mechanical prophylaxis (options)
- SCD
- Graduated compression stockings
activity level/exercise
►
►
►
AGENTS ASSOCIATED
WITH INCREASED RISK
Chemotherapy
Exogenous estrogen
compounds
- HRT
- Oral contraceptives
- Tamoxifen/Raloxifene
- Diethystilbestrol
Thalidomide/lenalidomide
NCCN Practice Guidelines
in VTE Disease
Inpatient Prophylactic Anticoagulation Therapy
► LMWH
- Dalteparin 5,000 units subcutaneous daily
- Enoxaparin 40 mg subcutaneous daily
- Tinzaparin 4,500 units (fixed dose) subcutaneous daily or
75 units/kg subcutaneous daily
► Pentasaccharide
- Fondaparinux 2.5 mg subcutaneous daily
► Unfractionated heparin 5,000 units subcutaneous 3 times daily
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
►
Should hospitalized patients with cancer
receive anticoagulation for VTE
prophylaxis ?
●
“Hospitalized patients with cancer should be
considered candidates for VTE prophylaxis in
the absence of bleeding or other
contraindications to anticoagulation”
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
►
Should ambulatory patients with cancer
receive anticoagulation for VTE
prophylaxis during systemic
chemotherapy?
●
“Routine prophylaxis is not recommended.”
●
“Patients receiving thalidomide or lenalidomide
with chemotherapy or dexamethasone are at high
risk for thrombosis and warrant prophylaxis.”
Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505.
►
Should hospitalized patients with cancer
undergoing surgery receive perioperative VTE
prophylaxis ?
●
All patients should be considered for
thromboprophylaxis.
Procedures greater than 30 minutes should receive
pharmacologic prophylaxis.
Mechanical methods should not be used as
monotherapy.
Prophylaxis should continue for at least 77-10 days
post--op. Prolonged prophylaxis may be considered
post
for cancer with high risk features.
●
●
●
Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505.
Compliance With ACCP VTE
Prophylaxis Guidelines Is Poor
Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group
62,012
70,000
At risk for DVT/PE
35,124
Received compliant care
Number of patients
10,000
9175
5,000
2324
1388
0
52.4%
Orthopedic
Surgery
15.3%
12.7%
At-risk Medical
Conditions
General
Surgery
9.9%
Urologic
Surgery
6.7%
Gynecologic
Surgery
Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based
on the 6th American College of Chest Physicians (ACCP) guidelines.
HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76
Reasons for Inadequate Duration
of VTE Prophylaxis
At
At--Risk Medical
(n=5,994)
Abdominal Surgery
(n=3,240)
Urologic surgery
(n=158)
Gynecologic surgery
(n=163)
Neurosurgery
(n=250)
Started Late
Started late &
Ended Early
Ended Early
1,347 (22.5)
2,961 (49.4)
1,686 (28.1)
824 (25.4)
1,764 (54.4)
652 (20.1)
18 (11.4)
73 (46.2)
67 (42.4)
13 (8.0)
43 (26.4)
107 (65.6)
66 (26.4)
125 (50.0)
59 (23.6)
HT Yu et al. Am J HealthHealth-Syst Pharm 2007; 64:69
64:69--76
Predictors of the Use of
Thromboprophylaxis
Effect
Odds Ratio (95% CI)
Malignancy
0.40
Others
0.58
Infection
0.83
Bleeding Risk
0.91
Gender
Hospital Size
0.92
0.93
Age
1.00
LOS
1.05
Cardiovascular Disease
1.06
Internal Medicine
1.33
Respiratory
1.35
AMC
Duration of Immobility
VTE Risk Factors
1.46
1.60
1.78
0.0 0.5 1.0
Kahn SR et Al. Thromb Res 2007; 119:145119:145-155
1.5 2.0 2.5
Odds Ratio
3.0 3.5 4.0
Computer Reminder System
►
Computer program linked to patient database to identify
consecutive hospitalized patients at risk for VTE
►
Patients randomized to intervention group or control group
►
In the intervention group the physicians were alerted to the VTE
risk and offered the option to order VTE prophylaxis
►
Point scale for VTE risk
● Major risk:
risk: Cancer
Cancer,, prior VTE, hypercoagulability
(3 points)
● Intermediate risk:
risk: Major surgery (2 points)
● Minor risk:
risk: Advanced age, obesity, bedrest, HRT,
use of oral contraceptives (1 point)
►
VTE prophylaxis (graduated
(graduated elastic stockings
stockings,, IPC, UFH,
LMWH, warfarin)
Kucher N, et al. N Engl J Med. 2005;352:9692005;352:969-77
MD Computer Alert
Electronic Alerts to Prevent VTE
Freedom from
DVT or PE (%)
100
98
96
Intervention group
94
92
Control group
P<0.001
90
88
0
Number at risk
Intervention group
Control group
30
1,255
1,251
Kucher N, et al. N Engl J Med. 2005;352:9692005;352:969-77
60
Time (days)
977
876
90
900
893
853
839
Mechanical Thromboprophylaxis In Critically Ill Patients:
Review And MetaMeta-analysis
RESULTS: 21 relevant studies (5 randomized controlled trials, 13
RESULTS:
observational studies, and 3 surveys) were found. A total of 811 patients
were randomized in the 5 randomized controlled trials; 3421 patients
participated in the observational studies.
Trauma patients only were enrolled in 4 randomized controlled trials and 4
observational studies. MetaMeta-analysis of 2 randomized controlled trials with
similar populations and outcomes revealed that use of compression and
pneumatic devices did not reduce the incidence of venous
thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).
A range of methodological issues, including bias and confounding variables,
make meaningful interpretation of the observational studies difficult.
CONCLUSIONS: The role of mechanical approaches to
CONCLUSIONS:
thromboprophylaxis for intensive care patients remains
uncertain
Limbus A et al. Am J Crit Care, 2006;15:4022006;15:402-10
Fatal Pulmonary Embolism During
Anticoagulant Prophylaxis
Study,
Prophylaxis
Year
(Reference)
Placebo
n/n
n/n
RR Fixed
RR Fixed
(95% CI)
(95% CI)
Dahan et al, 1986 (41)
1/132
3/131
0.33 (0.03 to 3.14)
Garlund at al, 1996 (35)
3/5776
12/5917
0.26 (0.07 to 0.91)
Leizorovic et al, 2004 (23) 0/1829
2/1807
0.20 (0.01 to 4.11)
10/1230
17/1244
0.59 (0.27 to 1.29)
0/321
5/323
0.09 (0.01 to 1.65)
Mahe et al, 2005 (22)
Cohen at, 2006 (42)
Total (95% CI)
Total events
0.38 (0.21 to 0.69)
14 39
0.001 0.01 0.1 1.0 10 100 1000
Favors Treatment
Dentali, F. et. al. Ann Intern Med 2007;146:2782007;146:278-288
Favors Placebo
Unfractionated Heparin Prophylaxis:
BID vs TID—
TID—What Works, What Doesn’t?
Meta-analysis: 12
MetaRCTs
► DVT,
PE, all VTE events, Bleeding
► Proximal
●
●
DVT plus PE
BID VTE event rate:
2.34 events per 1,000
patient days
TID event rate:
0.86 events per 1,000
patient days
P=0.05
► NNT
●
●
676 hospital prophylaxis days
with UFH TID to prevent
1 major bleed with 1,649 hospital
prophylaxis days of TID dosing
King CS et al. CHEST 2007;131:5072007;131:507-516
Heparin, Low Molecular
Weight Heparin Prophylaxis
►Meta
Meta--analysis
►36
randomized
controlled trials
►23,000 hospitalized
medical patients
►UFH 5,000 units TID
is more effective in
preventing DVT than
UFH BID
►Low molecular weight
heparin is 33% more
effective than
unfractionated heparin
in preventing DVT
● RR for DVT 0.68
(p=0.004)
LMWH vs UFH
DVT
Risk
Study
Reduction (95% CI)
Weight %
Harenberg et al, 1990
0.70 (0.16-3.03)
3.4
Turpie et al, 1992
0.29 (0.10-0.81)
11.4
Dumas et al, 1994
0.74 (0.38-1.43)
14.4
Bergmann & Neuhart
0.94 (0.39-2.26)
8.1
Harenberg et al, 1996
2.89 (0.30-27.71)
0.8
Lechler et al, 1996
0.25 (0.03-2.23)
3.3
Hillbom et al, 2002
0.55 (0.31-0.98)
20.5
Kleber, et al 2003
0.77 (0.43-1.38)
19.4
Diener et al, 2006
0.76 (0.42-1.38)
18.9
Overall (95% CI)
0.68 (0.52-0.88)
et al, 1996
Wein L et al. Arch Intern Med. 2007;167:1476
2007;167:1476--86.
0.1
1.0
10
Risk Ratio
LMWH Better
LMWH Worse
BWH/DFCI Partners
Cancer Care Experience
Reasons for Non-Compliance
100
90
80
70
60
50
40
30
20
10
0
95
80
82
68
70
60
29
Percent
Percent
Compliance with UFH TID
50
40
28
30
20
<3
doses
Day 1
<3
Doses
Day 2+
• Consecutive
4 doses
10
4
0
Off Floor
Refused
patients, < 60 days
• 2 Nursing units
• LOS ranged from 3 days to 31 days
• Number of days where doses were omitted ranged from
1 to 6 days
Unknown
VTE Incidence: More Common
in the Outpatient Setting
►
Medical records of residents (n=477,800)
►
587 VTE events (104 per 100,000 population)
►
30 Day recurrence 4.8 %
VTE Event Location
25%
75%
Inpatient
Outpatient
Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777
52%
51%
51%
50%
50%
49%
49%
48%
Patients receiving prophylaxis
during high risk periods
Prophylaxis
None
Antithrombotic Therapy Practices
in U.S. Hospitals
►Survey
►n=939
DVT or PE
60%
Percent (%)
of 38 U.S.
Hospitals
70%
40%
patients
reached INR >2 for
2 consecutive days
26.6%
30%
20%
10%
►50%
50.7%
50%
14.8%
7.9%
0%
Acute (n=72)
Bridge (n=241)
Long Term
(n=460)
Other (n=134)
Therapy
14
12.7
Therapy
n (%)
LMWH
527 (56.1%)
UFH
562 (59.8%)
UFH SC
78 (8.3%)
DTI
6 (0.6%)
LO S, Days
12
10
8
8.1
6.1
6
4
4
2
0
Acute
(n=72)
Tapson V et al. Arch Intern Med 2005
Bridge
(n=241)
Long term
(n=460)
Other
(n=134)
Self--Managed Long Term LMWH Therapy
Self
2212 patients with proximal vein thrombosis assessed
for eligibility
1475 excluded for
anticoagulant violations
or inability to give
written consent
737
Randomized
369 assigned to LMWH
369 assigned to usual care with
heparin & warfarin
3 lost to follow=up
3 lost to follow-up
1 withdrew consent
5 withdrew consent
369 included in Analysis
Hull R. Am Jour Med 2007; 120:72120:72-82
369 included in Analysis
Self--Managed Long Term LMWH Therapy
Self
Tinzaparin
Usual Care
Absolute Difference
(n=369)
(n=368)
(95% CI)
New VTE at 3 Mos
18 (4.9)
21 (5.7)
-0.8 ((--4.24.2-2.4)
NS
New VTE at 12 Mos
33 (8.9)
36 (9.8)
-0.8 ((--5.55.5-3.5)
NS
All Bleeding
48 (13.0)
73 (19.8)
-6.8 ((--12.4
12.4---1.5)
p=.011
Major Bleeding
12 (3.3)
17 (4.6)
-1.4 ((-4.34.3-1.4)
NS
Minor Bleeding
36 (9.8)
56 (15.2)
-5.5 ((--10.4
10.4---0.6)
p=.022
Stratified BleedingBleedingHigh Risk
31/144 (21.5)
39/146 (26.7)
-5.2 ((--15%
15%--4.6%)
NS
Stratified BleedingBleeding-Low
Risk
17/225 (7.6)
34/222 (15.3)
-7.8 ((--13.6
13.6---1.9%)
p=.01
Thrombocytopenia
(<150)
21 (5.7)
9 (2.4)
1.6 ((-3.63.6-0.3)
NS
Bone Fracture
4 (1.1)
7 (1.9)
-0.8 ((--0.90.9-2.6)
NS
Outcomes
Hull R. Am Jour Med 2007; 120:72120:72-82
p-value
LMWHs and Bleeding in Patients
with Renal Dysfunction
Dosage adjustments
for renal dysfunction
Lim W et al. Ann Intern Med 2006; 144:673144:673-84
Conclusions
Examine your current practices of VTE
prophylaxis and treatment
► Review available guidelines as a benchmark
► Consider the use of a pharmacologic or
mechanical intervention
► Evaluate use of Reminder or Risk Scoring
Systems
► Utilize the regimen providing the best efficacy in
reducing events and offering best compliance
► Follow
Follow--up with patients to monitor and avoid
adverse events and to ensure optimal outcomes
Dosaggio dei D-Dimeri
• Prodotti di degradazione della fibrina stabilizzata
• Elevati livelli plasmatici di DD, oltre che per la presenza
di trombi (sia venosi che arteriosi), possono essere
frequentemente causati da molte altre condizioni come
ematomi sottocutanei, ferite chirurgiche, necrosi
cutanea, ustioni estese, ascite, versamenti pleurici.
• Un aumento dei DD si osserva con estrema frequenza in
una grande varietà di situazioni cliniche (CID, neoplasie,
angina instabile, infarto miocardico, eclampsia, infezioni,
malattie epatiche e renali, chirurgia).
Linee guida SISET-SIAPAV-SIDV 2000 – CIF 2000-2003
Trousseau’s Observations (continued)
“There appears in the cachexiae…a
particular condition of the blood that
predisposes it to spontaneous
coagulation.”
Lectures in Clinical Medicine, 1865
Interface of Biology and Cancer
Tumor cells
Angiogenesis,
Basement matrix
degradation.
Fibrinolytic
activities:
t-PA, u-PA, u-PAR,
PAI-1, PAI-2
Procoagulant Activities
IL-1,
TNF-α,
α,
VEGF
PMN leukocyte
Activation of
coagulation
FIBRIN
Platelets
Monocyte
Endothelial cells
Falanga and Rickles, New Oncology:Thrombosis,
Oncology:Thrombosis, 2005; Hematology, 2007
VTE is frequent and serius
Patient Related
•
•
•
•
Increased Age
Obesity
Co-morbidities
Performance Status
Treatment Related
• Chemotherapy, antiangiogenesis
agents, hormonal therapy
• Radiation therapy
• Surgery
• Indwelling venous access
Risk
Factors
Cancer Related
•
•
•
•
Primary Site
Stage
Histology
Time since diagnosis
Biomarkers
• Platelets > 350 x 109/L
• Leukocyte count > 11x 109/L
• Hgb < 10 g/dL
Cancer and Thrombosis